The Complement System

1. The Complement System

2. Contents Concepts Complement Activation Regulation of the Complement System Biological Function of Complement

3. Concepts 1. Simple history of complement research 1890 Behring antitoxin 1894 Pfeiffer temperature sensitive component in serum necessary for bacteriolysis 1894 Bordet alexin (1920 Nobel prize) 1894 Ehrlich complement Ab to cause bacterolysis 1907 Ferrata C1, C2 1912 Ritz C3 1926 Gorder C4 1969 Muller-Eberhard Classical pathway

4. 1895 Bordet: the experiment of the lysis of Vibrio cholerae

5. Presumption: • There is a component in the fresh serum that helps the antibody to lyse the bacteria. • The chemical property of this component is not stable. • This component is not antigen specific.

6. The complement is a group of temperature sensitive protein existing in the serum and tissue fluid of human and vertebrate. • After activated, they have enzymatic activity. • They are the major molecules of the innate immune system.

7. 2. Components of the Complement System (1) Complement Components: C1-9, MBL , SP , Bf , Df (2) Regulatory Proteins: Properdin , C1INH , C4bBp , Hf, If , CR1 , Sp (3) Complement Receptor: CR1-CR5 , C2aR , C3aR , C4aR

8. Complement Components involved in the classical pathway (the components were named in order of their discovery)

9. 3. Denomination of the components of the complement system • With enzymatic activity after activation: C1, C4b2b • Peptide fragmentsformed by activation of a component: C3a, C3b (the smaller fragment is designated “a” and the larger fragment designated “b”) • Inactivated components: iC2a • Factors: B, P (capitalization)

10. 4. Basic Characteristics of Complement • The complement componentsinteract in a highly regulated cascade. • Complement serves by amplifying the response: C1q, C3 convertase • Unstability: 56°C, 30min • Dualism of the functions: physiological functions, pathological functions • Restriction of reaction: easy to be inactivated, antibody, suppression component

11. Complement Activation 1. classical pathway 2. alternative pathway 3. lectin pathway

12. Complement Activation 1. classical pathway a. activator IC (immune complex) polymerizer (heparin, polynucleotide) dextran sulfate protein (CRP) liposome mitochondria of cardiac muscle

13. 1. classical pathway b. activation condition The formation of an antigen-antibody complex induces conformational changes in the Fc portion of the Ab molecule that expose a binding site for the complement. C1 binds to exposed C1q-binding sites inthe CH2 domain of IgG1-3 or the CH3 domain of IgM. C1 binds to at least two Fc portions of Ab.

16. C1q (1) the biggest molecular weight, composed of 18 polypeptide chains that associate to form six collagen-like triple helical arm (2) the only component of complement that circulate in the serum in functionally active forms (3) For activation, it need to bind to at least two IgG or one IgM and need the presence of Ca2+. (4) Free or soluble Ab can not bind to the complement; the formation of an antigen-antibody complex induces conformational changes in the Fc portion of the Ab molecule.

18. 1. classical pathway c. activation stage recognition stage: IC-C1 activation stage: C1s→C4, C2→C3, C5 attack stage: C5b→C5678(9)n (MAC)

23. Complement Activation 2. alternative pathway a. activator LPS bacteria zymosan dextran IgA IgG4 IgE

24. 2. alternative pathway b. characteristics: non-specific, rapid distinguish self and non-self C3b positive feedback need a surface to stick or activate C3b

25. 2. alternative pathway c. activation stage formation of C3bBb activation stage C3→C5 attack stage: C5b→C5678(9)n (MAC)

27. alternative pathway

28. Complement Activation 3. lectin pathway, MBL a. activator: MASP (MBL:SP) b. activation stage formation of MASP: cleave C4, C2 activation stage: C3→C5 attack stage: C5b→C5678(9)n (MAC)

29. lectin pathway

30. Overview of the complement activation pathways.

31. membrane attack complex, MAC Composition: C5b678 (9)n , 12-15 C9 Size: 10-11 nm inner diameter Effects: This complex forms a large channel through the membrane of the target cell, enabling ions and small molecules to diffuse freely across the membrane.

35. Regulation of the Complement System 1. Short half-life 2. Regulation protein up-regulation: Properdin, C3Nef down-regulation:C1INH, C4bBp, Hf, If, DAF, CR1, MCP

36. Regulation of the Complement System

37. Biological Function of Complement 1. bacteriolysis, cytosis 2. function of complement fragments a. opsonization: C3b, iC3b, C4b b. mediator of inflammation: C3a, C4a, C5a c. kinin: C2a, C5a d. chemotaxis: C3a, C5a, C567 3. C-dependent virolysis 4. clean up IC: interfere with the formation of IC, IC-C3b-CR1-RBC 5. immunological regulation: C3, CR1, CR2, C3b

40. Complement and Clinic 1. Complement deficiencies 2. Serum complement level and disease 3. Pathological damage by complement 4. Clinical application of complement

41. Diseases about Complement deficiencies Proteins in defect Functions influenced Diseases C1, C2 , C4 deficiency in cleanup of IC SLE, pyogenic infection deficiency in the activation of classical pathway C3 inability of cleanup of IC SLE, pyogenic infection complement activation glomerular nephritis C1INH loss of control in the production hereditary angiodysplasia of inflammatory mediators factor Hloss of control in the activation SLE, pyogenic infection of alternative pathway glomerular nephritis low concentration of C3 in the serum DAF, CD59cytotoxic function of complement paroxysmal nocturnal to host cell hemoglobinuria CR3 deficiency in adhesion of PBMC infection (aeruginosus Bacillus, pseudomonad etc.)

42. *** Definition, basic characteristics and components of complement *** Characteristics of complement activation and the sameness and differentia of three complement activation pathways ** Biological Function of Complement ** Regulation of the Complement System and its significance * Key biological significance of complement receptor and membrane-binding protein * Relation between complement system and diseases